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High-alert medications for pediatric patients: An international modified

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High-alert medications for pediatric patients: an

international modified Delphi study
a bd c
Jolanda M Maaskant RN MSc , Anne Eskes RN PhD , Petra van Rijn-Bikker PharmD , Diederik
a a bd
Bosman MD PhD , Wim van Aalderen MD PhD & Hester Vermeulen RN PhD
a
Emma Children's Hospital, Academic Medical Center, PO Box 22660, 1100 DE Amsterdam,
the Netherlands +31205668173; +31206917735;
b
Academic Medical Center, Department of Quality Assurance and Process Innovation,
Amsterdam, the Netherlands
c
Academic Medical Center, Department of Clinical Pharmacy, Amsterdam, the Netherlands
d
Department of Nursing of the Amsterdam School of Health Professions, Amsterdam, the
Netherlands
Published online: 10 Aug 2013.

To cite this article: Jolanda M Maaskant RN MSc, Anne Eskes RN PhD, Petra van Rijn-Bikker PharmD, Diederik Bosman MD PhD,
Wim van Aalderen MD PhD & Hester Vermeulen RN PhD (2013) High-alert medications for pediatric patients: an international
modified Delphi study, Expert Opinion on Drug Safety, 12:6, 805-814

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 Original Research

High-alert medications
for pediatric patients:
an international modified
1. Introduction
2. Methods
Delphi study
3. Results Jolanda M Maaskant†, Anne Eskes, Petra van Rijn-Bikker, Diederik Bosman,
4. Discussion Wim van Aalderen & Hester Vermeulen
†
5. Conclusions Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands

Background: The available knowledge about high-alert medications for chil-

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dren is limited. Because children are particularly vulnerable to medication

errors, a list of high-alert medication specifically for children would help to
develop effective strategies to prevent patient harm. Therefore, we con-
ducted an international modified Delphi study and validated the results
with reports on medication incidents in children based on national data.
Objective: The objective of this study was to generate an internationally
accepted list of high-alert medications for a pediatric inpatient population
from birth to 18-years old.
Results: The rating panel consisted of 34 experts from 13 countries. In total,
14 medications and 4 medication classes were included with the predefined
level of consensus of 75%. The high-alert medications were: amiodarone,
digoxin, dopamine, epinephrine, fentanyl, gentamycin, heparine, insulin,
morphine, norepinephrine, phenytoin, potassium, propofol and tacrolimus.
The high-alert medication classes included in the final list were: chemothera-
peutic drugs, immunosuppressive medications, lipid/total parenteral nutrition
and opioids.
Conclusion: An international group of experts defined 14 medications and
4 medication classes as high-alert for children. This list might be helpful as a
starting point for individual hospitals to develop their own high-alert list
tailored to their unique situation.

Keywords: children, harm, high-alert, medication safety, pediatrics

Expert Opin. Drug Saf. (2013) 12(6):805-814

1. Introduction

Patient harm as a result of medication errors (MEs) is one of the most common type
of adverse events in hospitalized patients [1]. Although MEs do not always cause
patient harm, studies have shown that 3 -- 10% of such errors result in significant
harm or even contribute to death [1-4]. Children are believed to be at especially
high risk of harm due to MEs; according to estimates, MEs result in harm in
children about three times more often than in adults [5]. Therefore, the safe use of
medication in children requires even more precautions than in adult patients.
It is important to note that not all adverse drug events are the result of MEs, and
are thus not preventable, but it is estimated that about 50% of them are [2,6,7]. Nev-
ertheless, until now interventions have led to only limited improvements, and MEs
continue to threaten patient safety [8].
Medications are very diverse and have a wide range of risk profiles. Those with a
heightened risk of causing patient harm are known as high-alert medications;
they have serious consequences for patients when misused [9]. Attention for

10.1517/14740338.2013.825247 © 2013 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 805
All rights reserved: reproduction in whole or in part not permitted
 J. M. Maaskant et al.
high-alert medications is stressed by several leading organiza-
tions like the Institute of Healthcare Improvement (IHI),
Joint Commission International (JCI) and the Institute of
Safe Medication Practice (ISMP) [9-11]. A list of high-
alert medications for the general patient population has been
developed by the ISMP, based on error reports and expert
opinions [9].
The available knowledge about high-alert medications for
children is limited. Analyses of pediatric MEs voluntary
reported in the USA and Canada have resulted in two slightly
different lists [12,13]. Although studies on MEs sometimes
report the medications involved, they seldom report the
ones that must be considered high-alert. Moreover, studies
that reported on high-alert medications in pediatric and
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neonatal intensive care units did not result in a uniform
list [14,15]. Because children are particularly vulnerable to
MEs, in clinical practice a list of high-alert medications
specifically for children would help to develop and implement
more effective strategies to prevent patient harm.
Therefore, we aimed to generate an internationally
accepted list of high-alert medications for an inpatient pedia-
tric population. The target group included all children from
birth until 18-years old without any underlying disease
or syndrome.
2. Methods
2.1 Study design
Our study consisted of two parts. First, we reviewed the liter-
ature to generate a preliminary list of high-alert medications
for children. Second, we used the modified Delphi technique,
which is considered to be an effective way to obtain consensus
within a group of experts [16]. High-alert medications are
defined as medications that are considered to cause patient
harm when misused due either to a narrow therapeutic win-
dow or to serious adverse events in the past. Harmful and
unintended responses to medications, at normal dosages and
proper use, known as adverse drug reactions or side effects,
are excluded from this definition.
The Institutional Review Board of the Academic Medical
Center in Amsterdam reviewed the protocol and judged that
it was not subject to medical ethical approval according to
the Dutch Medical Ethics Law. All responses were analyzed
and reported anonymously.
Review of literature reporting high-alert
2.2
medication
We reviewed the literature to generate a list of possible high-
alert medications. For this purpose, we systematically searched
the Cochrane Library, MEDLINE and EMBASE to identify
studies published until 1 February 2012. We included all
publications that aimed to describe high-alert medications
because they were identified or considered to be harmful in
hospitalized children from birth to 18-years old. No
806 Expert Opin. Drug Saf. (2013) 12(6)
limitations were applied to study design, publication date or
language. We excluded publications investigating safety pro-
files of predefined medications. We conducted a purely
descriptive review and, therefore, did not assess the publica-
tions on study quality. The results of this review were used
as the starting point for the Delphi rounds.
2.3 Expert group
Prospective members of the international expert group were
identified through literature review, websites of medication
safety organizations and recommendations from known
experts in the field. In addition, we applied the following
inclusion criteria: health care professionals were qualified as
experts if i) they had at least 5-years post-qualification experi-
ence in pediatrics, ii) were educated to postgraduate level and
iii) were willing to participate. We included pediatricians,
neonatologists, anesthetists, pharmacists and pediatric nurses.
To improve the generalizability and usefulness of our final
list, we aimed to create a sample of representative experts,
homogeneous in the field of medication safety issues, but
from various geographical regions. We aimed to include at
least 30 experts to assure sufficient expertise and representa-
tiveness, even if attrition occurred [17]. We sent a letter by
email to the experts to explain the aim of this study and the
study design, and to request their participation. After
informed consent, the experts received three web-based
questionnaires, one for each Delphi round. We also collected
data on the experts, such as their profession, education, years
of experience and employment or designation. To prevent
attrition, we aimed at a quick turnaround time, used person-
alized emails, reminded non-responding experts by email and
gave deadlines [18].
2.4 Data collection
Data were collected by questionnaire, one for each round.
The questionnaires were pretested in a pilot study. To this
end, we sent the web-based questionnaires to a pediatrician,
a neonatologist, a pharmacist and a nurse. We asked them
to comment on the content, clarity and phrasing of the ques-
tions as well as the layout of the questionnaire. The comments
were used to improve the questionnaires. The participating
experts received the link for the online questionnaire by email,
using a commercial available survey tool (SurveyMonkey, Inc.
Europe, Sarl, Luxembourg). The three questionnaires were
distributed in May, June and July 2012. The questionnaires
included instructions for completion. The experts were asked
to respond within 3 weeks. Up to two reminders were sent per
round to non-responders. The second and third question-
naires were send within 1 week after the previous round
was finished.
During all rounds the experts were asked to rate their opin-
ions on a 5-point Likert scale: ‘strongly disagree’, ‘disagree’,
‘neutral’, ‘agree’ and ‘strongly agree’. Because no standard
threshold for consensus exists [19], we used the following

definition: at least 75% of the experts rated a medication as
high-alert with ‘agree’ or ‘strongly agree’. Consequently, if at
least 75% of the experts rated ‘disagree’ or ‘strongly disagree’,
then the corresponding medication was excluded from
further discussion.
2.5 Delphi rounds
The first questionnaire consisted of three parts. The first part
posed questions about the baseline characteristics of the
experts. In the second part, we presented a list of possible
high-alert medications generated from the literature review.
We presented the list alphabetically and included a brief sum-
mary of the relevant literature. The first question was to rate
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the medication as high-alert. In addition, we collected infor-
mation regarding the patient age groups, routes of administra-
tion and the organ systems in which adverse events might
occur in case of misuse. This additional information was col-
lected only during the first round. In the third part of the
questionnaire, the experts were asked to add any medications
or medication classes that they considered to be high-alert if
they were not included on the initial list. The experts were
given the option of supporting their choices with scientific
evidence, incident reports or experience. Medications on
which consensus was reached in Delphi round 1, based on
the 75% level of agreement, were not discussed again in
Delphi round 2.
Medications on which no consensus was reached, together
with the additional medications suggested in Delphi round
1, were included in the second questionnaire. Once again,
the list of medications was alphabetical. The medications
rated in the first round were listed with the group response
results, described as percentages of the experts’ scores on the
5-point Likert scale. We asked the experts to rate each medi-
cation on which no consensus was reached, as well as the
newly added medications. Medications on which consensus
was reached in Delphi round 2 were not discussed again in
Delphi round 3. In addition, the medications that had been
rated by the experts in the first two rounds were not presented
again in Delphi round 3.
We asked the experts to once again rate the medications
that remained from Delphi round 2. We presented the list
in alphabetical order. The experts were asked to rate the
medication as high-alert according the 5-point Likert scale,
as in previous rounds.
2.6 Validation
We validated our results with reports on medication incidents
in children. For this purpose, we used data from the Dutch
incident registration (Foundation Portal for Patient Safety/
CMR). CMR is a nonprofit organization devoted entirely to
the nationwide registration and prevention of adverse events
in health care, using a voluntary incident reporting system.
These incident reports are used to learn about errors, under-
stand their causes and share this information with health
Expert Opin. Drug Saf. (2013) 12(6)
High-alert medications for pediatric patients
care professionals across the country. ME prevention and
safe medication use is a main focus of the organization.
2.7 Data analyses
Descriptive statistics were used to report our results. We
expressed the level of agreement in percentages of same
answers to each question. Medications rated as ‘strongly agree’
or ‘agree’ by at least 75% of the experts were included in the
final list. We excluded medications that were rated as ‘strongly
disagree’ or ‘disagree’ by 75% of the experts. To analyze the
change in answers towards consensus, we described the dis-
persion of the results in standard deviations (SD) and ranges.
All analyses were performed using SPSS software (PASW
statistics version 18.0, IBM, Armonk, NY, USA).
3. Results
Review of literature reporting high-alert
3.1
medication
The literature search yielded 76 titles. After independently
screening on titles and abstracts, we excluded 63 publications
because they did not report on high-alert medications, did
not involve a pediatric population and/or were not per-
formed in a hospital setting. Consequently, 13 publications
were selected for further study [14,15,20-30]. A manual search
of the references in these articles yielded two additional pos-
sibilities [12,31]. After studying the full text of the articles, we
excluded 11 publications [20-31], leaving 4 publications that
met our inclusion criteria [12-15]. Patient and medication
characteristics were summarized, resulting in an initial list
of 16 high-alert medications in children. This initial list,
with a short summary of the literature, was used in the
Delphi process.
3.2 Expert group
We invited 92 experts to participate, of whom 34 gave
informed consent. Experts who replied that they did not
want to participate, or who did not respond to our invita-
tion, were removed from the mailing list. As summarized
in Table 1, our expert group from 13 countries included
pediatricians, a neonatologist, an intensivist, pharmacists
and pediatric nurses. Regarding postgraduate experience,
62% the experts reported > 15 years. Of the total group of
34 experts, 30 responded (88%) in the first round,
27 responded (79%) in the second round and 30 responded
(88%) in the third round. In total, 25 experts completed all
three questionnaires (74%). One expert did not respond at
all (2%).
3.3 Delphi rounds
In the first round, we presented 16 medications to the experts.
Consensus was achieved on 8 medications, which were then
included in the final list: digoxin, dopamine, epinephrine,
fentanyl, heparine, insulin, morphine and potassium. No
807
 J. M. Maaskant et al.

Table 1. Baseline characteristics of the experts.

Number of experts Total Round 1 Round 2 Round 3

n % n % n % n %

34 100 30 88 27 79 30 88

Country
Belgium 2 6 2 7 2 7 2 7
Canada 1 3 1 3 1 4 1 3
Estonia 1 3 1 3 -- -- 1 3
Germany 1 3 1 3 1 4 1 3
Ireland 1 3 1 3 1 4 1 3
Italy 1 3 1 3 -- -- 1 3
Latvia 1 3 1 3 1 4 1 3
Luxembourg 1 3 1 3 1 4 1 3
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the Netherlands 7 21 5 17 5 18 5 17
Norway 1 3 1 3 1 4 1 3
Slovenia 1 3 1 3 -- -- -- --
UK 10 29 10 33 9 33 10 33
USA 6 18 4 14 5 18 5 17
Profession
Pediatrician 12 35 10 33 8 29 10 33
Neonatologist 8 24 8 27 6 22 8 27
Intensivist 1 3 1 3 1 3 1 3
Pharmacist 9 24 9 30 9 33 7 23
Nurse 4 15 2 7 3 11 4 14
Postgraduate experience*
5 -- 10 years 1 3 1 3 1 4 1 3
10 -- 15 years 10 29 10 33 10 37 10 33
> 15 years 21 62 19 64 16 59 19 64
Highest level of education
Bachelor’s degree 1 3 1 3 1 4 1 3
Master’s degree 6 18 3 10 4 15 2 7
Post-master’s degree (PhD) 12 35 11 37 9 33 12 40
Professor 11 32 11 37 9 33 11 37
Otherz 4 12 4 13 4 15 4 13
Organization
Academic Hospital 19 56 18 60 16 59 16 53
Teaching Hospital 5 15 4 13 4 15 5 17
University 4 12 3 10 2 7 3 10
Other§ 6 18 5 17 5 19 6 20

*Information of two experts missing.

z
Doctor of Medicine (MD), Doctor of Pharmacy, post-graduate degree Clinical Pharmacology.
§
Non-teaching hospital, Nonprofit research foundation, Research consultancy, (National) regulatory agency.

medications were excluded. The experts added 23 high-alert
medications and 7 high-alert medication classes.
In the second questionnaire, we included the 8 medications
remaining from the first round for further consensus dis-
cussion, along with the 23 additional medications and 7 med-
ication classes suggested in the first round. Consensus was
achieved on 2 of these medications (gentamycin and propo-
fol) and 2 medication classes (chemotherapeutic drugs and
opioids), which were then included on the final list. Once
again, no medications were excluded.
In the third questionnaire, we included the 22 medications
and 5 medication classes that remained from the first
two rounds. In this final round, consensus was achieved on
4 additional medications (amiodarone, norepinephrine,
phenytoin, tacrolimus) and 2 medication classes (immuno-
suppressive medications and lipid/total parenteral nutrition).
The results are summarized in Figure 1.
3.4 Final list
The experts reached consensus on 14 medications and 4 med-
ication classes. The final list of medications included amiodar-
one, digoxin, dopamine, epinephrine, fentanyl, gentamycin,
heparine, insulin, morphine, norepinephrine, phenytoin,
potassium, propofol and tacrolimus. The final list of medica-
tion classes included chemotherapeutic drugs, immunosup-
pressive medications, lipid/total parenteral nutrition and
opioids. The consensus level ranged between 75 and 100%.
Based on the predefined threshold of 75%, we excluded

808 Expert Opin. Drug Saf. (2013) 12(6)

 High-alert medications for pediatric patients

Records identified through database Additional records identified through

literature review
search other sources
(N = 76 ) (N = 2)

Publications included in the review

(N = 4)
Delphi round 1

Response rate 88%

consensus on 8 medications
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31 medications and 7
medication classes included
in the second questionnaire
(n = 121)
Delphi round 2

Response rate 79%

consensus on 2 medications and
2 medication classes

22 medications and 5
medication classes included
in the third questionnaire
Delphi round 3

(n = 121)

Response rate 88%

consensus on 4 medications and
2 medication classes

Figure 1. Study flow.

25 medications and 3 medication classes from the final list.
The results are summarized in Tables 2 and 3.
3.5 Additional information
The experts considered the listed medications to high-alert for
all routes of administration, but considered intravenous
administration as an increased risk for patients. Regarding
the age of the patients, most experts considered the included
medications to be high-alert for all ages. Neonates and infants
were believed to be at higher risk than older children. The
experts also indicated the organ systems which are most
affected in case of misuse. These results are summarized
in Table 4.
We analyzed the process of reaching consensus by compar-
ing the dispersion of the results between the first and second
experts’ opinions. The mean SD changed from 0.98 to
0.75 and the mean range changed from 3.29 to 2.89. This
indicates that during the Delphi process the variation in the
opinions decreased and the consensus increased.
3.6 Validation
We analyzed all medication incident reports for children from
43 hospitals in the Netherlands, submitted to the CMR in the
period April 2010 to September 2012. In total, 1064 reports
were analyzed regarding medication and patient harm related
to the incidents. Of the 18 medications and medication clas-
ses on the high-alert list, 4 (22%) were confirmed with inci-
dents that resulted in serious temporary harm or worse,
while 9 (50%) were confirmed with incidents that were con-
sidered potentially harmful, that is they could have resulted
in serious temporary harm or worse.
4. Discussion
In this Delphi study, experts from 13 countries generated a
list of high-alert medications for a pediatric inpatient popula-
tion. Such medications are considered to cause patient harm

Expert Opin. Drug Saf. (2013) 12(6) 809

 J. M. Maaskant et al.

Table 2. High-alert medications, consensus $ 75%.

Medications
Gentamycin* 100% Dopamine* 83%
Digoxine 93% Tacrolimus 83%
Norepinephrine 93% Phenytoin* 83%
Potassium* 89% Insulin* 79%
Amiodarone 87% Morphine* 79%
Epinephrine* 86% Heparine* 75%
Propofol 84% Fentanyl* 75%
Medication classes
Chemotherapeutic drugs* 84% Lipid/total parenteral nutrition* 79%
Immunosuppressive drugs* 86% Opioids* 76%

*Considered high-alert in the Dutch medication incident reports system.

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Table 3. High-alert medications, consensus < 75%.

Medications
Calcium 74% Domperidone 30%
Epoprostenol 73% Methylphenidate 30%
Theophylline 73% Salbutamol 30%
Vancomycin 70% Acetylsalicylic acid 20%
Phenobarbital 70% Dexamethasone 20%
Dinoprostone/alprostadil 63% Ibuprofen 20%
Midazolam 63% Iron dextran 20%
Paracetamol/acetaminophen 43% Linezolid 17%
Propanolol 41% Ceftriaxon 11%
Risperidone 40% Fytomenadion 10%
Escitalopram 37% Montelukast 7%
Sodium bicarbonate 37% Spirolactone 7%
Dextrose > 20% 33%
Medication classes
Anti epileptic drugs 66% Anti hypertensive drugs 28%
ADHD medications 35%

when misused due either to a narrow therapeutic window or
to serious adverse events in the past.
Our finding that epinephrine [4,9,14], norepinephrine [9] and
dopamine [9,12,14,15] should be considered as high-alert medi-
cations for children is consistent with previous publications.
We also found a high level of consensus on the medication
class opioids [9,32,33], and more specifically for the medications
morphine [4,32] and fentanyl [12-15]. In addition, the medica-
tions digoxin [4,9,14,15,34], heparine [4,9,12,14,15,35], insulin [9,12-15]
and potassium [9,12-14,36] have been reported as high-alert in
several publications. Chemotherapeutic drugs [9], total paren-
teral nutrition [4,9,37], amiodarone [9] and propofol [9] were
also identified previously as high-alert, and fatal incidents
were reported on tacrolimus and phenytoin [4]. However, we
did not find any publications that described gentamycin and
the medication class immunosuppressive drugs as high-alert.
Despite the fact that salbutamol [12,13], ceftriaxone [12] and
propanolol [15] have been reported as high-alert medications
for children, we reached only limited consensus on these
medications in our study.
We compared the medications defined as high-alert in our
study to the list of high-alert medications of the ISMP. Out of
the 14 medications on our list, 11 are also on the ISMP list.
Moreover, 3 of the high-alert medication classes on our list
are similar to the medication classes on the ISMP list [9].
The limited consensus on several medications might be
explained by the international character of the expert group,
reflecting different medication practices in their countries of
origin. Therefore, it is important to realize that many factors
contribute to the risk profile of a medication, such as the toxic
features, the availability of more than one preparation or
dose strength of the same medication, the availability of
preparations for different routes of administration of a same
medication, dosages that require conversion of unit, calcula-
tions or serial dilutions. The high-alert classification is also
dependent on dosage, the familiarity of the health care profes-
sionals with the medication and the possibility of careful
monitoring. These situations might differ in various coun-
tries, resulting in different risk profiles for the same medica-
tion. Consequently, despite the absence of full consensus, it

810 Expert Opin. Drug Saf. (2013) 12(6)

 High-alert medications for pediatric patients

Table 4. Systems in which dysfunction might occur*.

Blood Cardiovasc. Digestive Endocr. Immune Metab. Nervous Respirat. Reprod. Urinary

Medications
Amiodarone -- 84% -- 37% -- -- -- -- -- --
Digoxine -- 100% 25% -- -- -- -- -- -- --
Dopamine -- 93% -- -- -- -- -- -- -- --
Epinephrine -- 92% -- -- -- -- 27% -- -- --
Fentanyl -- 48% -- -- -- -- 63% 82% -- --
Gentamycin -- -- -- -- -- -- 39% -- -- 87%
Heparine 96% -- -- -- -- -- -- -- -- --
Insulin -- -- -- 93% -- -- 26% -- -- --
Morphine -- 42% -- -- -- -- 69% 81% -- --
Norepinephrine -- 95% -- -- -- -- -- -- -- --
Phenytoin -- 27% -- -- -- -- 67% -- -- --
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Potassium -- 96% -- -- -- -- -- -- -- --
Propofol -- 77% -- -- -- 29% 35% 35% -- --
Tacrolimus -- 33% -- -- 73% 27% -- -- -- 40%
Medication classes
Chemotherapeutic drugs 80% 60% 40% 33% 73% 47% 60% 60% 60% 33%
Immunosuppressive drugs 33% -- -- -- 75% 33% -- -- 33% --
Lipid/total par. nutrition 36% 29% 36% -- 36% 93% -- -- -- --
Opioids -- 35% 29% -- -- -- 59% 77% -- --

Only scores ‡ 25% are presented.

*Percentage of experts that consider the medication (group) high-alert, because misuse might result in dysfunction of the mentioned systems.

is still necessary to evaluate the risk profiles of the excluded
medications on a national and institutional level.
The list, resulted from this study, should be used only as
a starting point as individual hospitals develop their own
high-alert list. Therefore, we stress a careful local review of
how the list relates to specific risks for a hospital. Error
reports, literature on medication safety and national incidents
registrations (if available) should be used to review the
hospital list on a regular base [11].
4.1 Delphi process
We performed an international modified Delphi study to
reach consensus on a subject on which empirical evidence is
difficult to collect. In this situation, the Delphi technique is
a validated and accepted methodology, because it gives equal
weight to the opinion of each expert and avoids domination
by one expert in the consensus process [19]. In addition, the
Delphi method allows anonymous participation of experts
across various countries and with different backgrounds [19].
Although our study consisted of three rounds, medications
and medication classes were only presented to the experts
twice. To explore the change in opinions towards consensus,
we followed the recommendations of Holey et al. and deter-
mined the SD and ranges that express the group agreement
in each round [38]. The decrease in SD and ranges between
the first and second expert ratings indicates a trend towards
consensus. Nevertheless, another round might have increased
the consensus even more.
Low response rates in research using questionnaires are a
recognized problem, and response rates lower than 70%
should be investigated for potential non-response bias [39].
Fortunately, we reached high response rates in every round
and, therefore, consider our results to be robust. Possible rea-
sons for the high response rate may be the explicit consent for
participation, resulting in a panel of experts who recognized
the importance of the topic and considered themselves to be
partners in this study. In addition, the quick turnaround
time, the clear timeframe and the personalized reminders
might have kept the experts interested.
Because no standard threshold for consensus was avail-
able [19], we based the 75% threshold in this study on face
validity of the results of the first round. Our final results
show that this threshold is disputable, with consensus levels
just under or just above the predefined threshold. Therefore,
we presented all medications with this level of consensus,
allowing health care professionals to consider the list in their
specific situations.
4.2 Experts
The heterogeneity of the experts in terms of profession and
country of origin made it potentially more difficult to achieve
consensus. However, the selection was based on what we
judged appropriate for an adequate, international representa-
tion, which we believe strengthens our findings. Although we
tried to have all continents represented, the experts in the
final group predominantly came from the USA, Canada or
European countries. Most participants originated from the
UK (29%), the Netherlands (21%) or the USA (18%). Experts
from Asia, South America, Africa and Oceania were absent in
our study. This could limit the generalizability of our results.

Expert Opin. Drug Saf. (2013) 12(6) 811

 J. M. Maaskant et al.
4.3 Validation
No standard exists to establish the validity of the Delphi
method, but it is assumed validity is part of the Delphi pro-
cess itself, due to successive rounds (concurrent validity) and
by achieving consensus within a group of experts (content
validity) [40,41]. In addition, we increased the credibility of
our results by comparing them with national medication
incidents in children that resulted in patient harm or were
reported as potential harmful.
4.4 Applications and suggestions for future research
Creating a list of high-alert medication alone does not prevent
patient harm. However, knowing which medications pose
serious risks to children allows health care organizations to
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develop and implement risk-reduction interventions. These
interventions should focus on additional safeguards through-
out the entire medication process for high-alert medications
and pay attention to the specific safety threats for children.
Several studies have demonstrated a reduction in MEs after
the introduction of a computerized physician order entry
system (CPOE) [42-44] and computerized clinical decision
support [42,45]. An additional strategy to reduce prescribing
errors could be to limit access to high-alert medication to spe-
cial trained and experienced staff, a measure that can be
implemented by special authorizations in CPOE. Further-
more, the prescribing stage of high-alert medication should
be supported by standardized prescriptions, a weight-based
dosage calculator and preventing over dosage by implement-
ing maximum dosing. In the administering stage risk reduc-
tion might be achieved by bar-code technology [46,47], that
also should be limited to special authorized staff in case of
high-alert medication. Additional risk-reduction measures in
the administering stage are described as ‘fail safes’, for exam-
ple smart pumps or different syringes for oral and intravenous
tubes [48]. The involvement of clinical pharmacists has proven
to increase medication safety [49,50]. They can play an essential
role in the medication process of high-alert medication by
performing the preparation of high-alert medication and
providing staff with timely consultation. Clinical pharmacist
also should initiate standardization and monitoring high-alert
medications. Double checking is assumed to reduce MEs and
is nowadays standard nursing policy [51]. Indeed, nursing staff
believe that double checking, if done properly, increases
medication safety. Unfortunately, practical problems hamper
the double checking process, for example interruptions, staff
shortages or an emergency situation, and some nurses prefer
double checking limited to high-risk patients and high-
alert medication [51,52]. Prevention strategies such as the use
812 Expert Opin. Drug Saf. (2013) 12(6)
of a unit dose dispensing system, dedicated nurses and the
involvement of parents might contribute to medication safety,
but robust evidence is limited [53-55].
Obviously, a fair number of risk-reduction strategies are
described, although some are considered more effective than
others [48]. For example, maximizing access to information
and limited access to high-alert medication seem to be better
safeguards than education and the use of reminders [48]. A
combination of different strategies is recommended to reach
an optimal effect, include all stages of the medication process
and reach all health care professionals involved [10,48]. In addi-
tion, interventions like executive walk rounds and communi-
cation tools, aiming to create a positive patient safety culture
should be considered, as this has been reported to be associ-
ated with enhanced patient safety [56,57]. Successful implemen-
tation of ISMP recommended high-alert interventions into
clinical practice have been reported [26,52]. The next step will
be to underpin these interventions and their implementation
with evidence, based on sound methodology [58].
Our list of high-alert medications should be viewed as a
dynamic list that needs regular updates. New medications,
new formularies and growing knowledge on medication safety
for children might have implications for the list presented in
our study. Sharing knowledge of harmful incidents, for exam-
ple through national incidents registrations, should be used as
a valuable supplement to scientific research.
5. Conclusions
In a three-round Delphi study, consensus was reached on
14 medications and 4 medication classes that are considered
high-alert for children. Medications and medication classes
on which consensus was less than our threshold of 75% still
might be handled as high-alert, depending on local situations.
Our results might be helpful as a starting point as individual
hospitals develop their own high-alert list.
Acknowledgements
We would like to thank the experts for taking part in the Del-
phi procedure (Appendix). We also thank E Zwart for helping
us identify experts and A van Rhijn and D Opstelten for their
support with the validation.
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.

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Affiliation
Jolanda M Maaskant†1 RN MSc,
Anne Eskes2,4 RN PhD,
Petra van Rijn-Bikker3 PharmD,
Diederik Bosman1 MD PhD,
Wim van Aalderen1 MD PhD &
Hester Vermeulen2,4 RN PhD
†
Author for correspondence
1
Emma Children’s Hospital,
Academic Medical Center,
PO Box 22660, 1100 DE Amsterdam,
the Netherlands
Tel: +31205668173;
Fax: +31206917735;
E-mail: j.m.maaskant@amc.nl
2
Academic Medical Center,
Department of Quality Assurance and Process
Innovation, Amsterdam, the Netherlands
3
Academic Medical Center,
Department of Clinical Pharmacy,
Amsterdam, the Netherlands
4
Department of Nursing of the Amsterdam
School of Health Professions, Amsterdam,
the Netherlands